Belén Palomares Martín Garrido‐Rodriguez Claudia Gonzalo‐Consuegra María Gómez‐Cañas Suwipa Saen‐oon Robert Soliva Juan A. Collado Javier Fernández‐Ruiz Gaetano Morello Marco A. Calzado Giovanni Appendino Eduardo Muñoz

Published in British Pharmacological Society 

June 2020


Background and Purpose

Δ9‐Tetrahydrocannabinolic acid (Δ9‐THCA‐A), the precursor of Δ9‐THC, is a non‐psychotropic phytocannabinoid that shows PPARγ agonist activity. Here, we investigated the ability of Δ9‐THCA‐A to modulate the classic cannabinoid CB1 and CB2 receptors and evaluated its anti‐arthritis activity in vitro and in vivo.

Experimental Approach

Cannabinoid receptors binding and intrinsic activity, as well as their downstream signalling, were analysed in vitro and in silico. The anti‐arthritis properties of Δ9‐THCA‐A were studied in human chondrocytes and in the murine model of collagen‐induced arthritis (CIA). Plasma disease biomarkers were identified by LC‐MS/MS based on proteomic and elisa assays.


Functional and docking analyses showed that Δ9‐THCA‐A can act as an orthosteric CB1 receptor agonist and also as a positive allosteric modulator in the presence of CP‐55,940. Also, Δ9‐THCA‐A seemed to be an inverse agonist for CB2 receptors. In vivo, Δ9‐THCA‐A reduced arthritis in CIA mice, preventing the infiltration of inflammatory cells, synovium hyperplasia, and cartilage damage. Furthermore, Δ9‐THCA‐A inhibited expression of inflammatory and catabolic genes on knee joints. The anti‐arthritic effect of Δ9‐THCA‐A was blocked by either SR141716 or T0070907. Analysis of plasma biomarkers, and determination of cytokines and anti‐collagen antibodies confirmed that Δ9‐THCA‐A mediated its activity mainly through PPARγ and CB1 receptor pathways.

Conclusion and Implications

Δ9‐THCA‐A modulates CB1 receptors through the orthosteric and allosteric binding sites. In addition, Δ9‐THCA‐A exerts anti‐arthritis activity through CB1 receptors and PPARγ pathways, highlighting its potential for the treatment of chronic inflammatory diseases such as rheumatoid arthritis.


Open Access




Palomares, B., Garrido‐Rodriguez, M., Gonzalo‐Consuegra, C., Gómez‐Cañas, M., Saen‐oon, S., Soliva, R., … & Appendino, G. (2020). Δ9‐Tetrahydrocannabinolic acid alleviates collagen‐induced arthritis: Role of PPARγ and CB1 receptors. British Journal of Pharmacology.